A Mechanistic Review on Protective Effects of Mangosteen and its Xanthones Against Hazardous Materials and Toxins

Due to its pharmacological properties, α-Mangostin, mainly found in Garcinia mangostana (G. mangostana) L. (Mangosteen, queen of fruits), treats wounds, skin infections, and many other disorders. In fact, α-Mangostin and other xanthonoid, including β-Mangostin and γ-Mangostin, are found in G. mangostana, which have various advantages, namely neuroprotective, anti-proliferative, antinociceptive, antioxidant, pro-apoptotic, anti-obesity, anti-inflammatory, and hypoglycemic through multiple signaling mechanisms, for instance, extracellular signal-regulated kinase1/2 (ERK 1/2), mitogen-activated Protein kinase (MAPK), nuclear factor-kappa B (NF-kB), transforming growth factor beta1 (TGF-β1) and AMP-activated protein kinase (AMPK). This review presents comprehensive information on Mangosteen's pharmacological and antitoxic aspects and its xanthones against various natural and chemical toxins. Because of the insufficient clinical study, we hope the current research can benefit from performing clinical and preclinical studies against different toxic agents.


INTRODUCTION
Nowadays, most chemicals and medicines have exhibited undesirable symptoms and the emergence of drug-resistant pathogenic bacterium, viruses, or fungi, toxic adverse effects of these chemicals, and withdrawal problems, limiting their administration in several countries [1][2][3].Hence, the herbal plants' study has produced present medicine with beneficial constituents that have been used to treat various diseases, especially in Africa and Asia [4][5][6][7].Also, they are easily accessible and cheap.Furthermore, many plant species have shown pharmaceutical activities because of the presence of many bioactive ingredients, for instance, flavonoids, alkaloids, steroids, glycosides, saponins, tannins, and terpenes [6][7][8][9][10][11]. Therefore, herbal medicines have been considered an essential source for finding new pharmaceutical molecules to treat serious diseases [3,9,12].Moreover, some research has proven that flavonoid and phenolic materials display *Address correspondence to this author at the International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran; Fax: +98 5138829279; E-mails: askariv@mums.ac.ir; vahidrezaaskary@yahoo.com;vahidrezaaskary@gmail.comanticancer, anti-inflammatory, antioxidant, and anti-diabetic activities [6,7,11,13,14].
G. mangostana L. (Mangosteen) is an evergreen tree and shrub native to the Philippines, India, Myanmar, Sri Lanka, Malaysia, and Thailand that belongs to the Clusiaceae family.This pyramidal crown tree can reach 6-25 m in height with glabrous, leathery leaves [15].The color of its fruit is dark purple or reddish, which has white, soft, and juicy edible pulp with acid and sweet flavor [16].The Mangosteendriven products classified 12 th in the United States upperselling supplements food products enriched with Mangosteen fruits gained 180 million dollars in the US in 2012 [17].As queen of fruits, Mangosteen has been used for medicinal purposes by Southeast Asians for centuries in the treatment of skin wounds (that is safe in 8% w/w concentration for skin use) [18] and infections [19,20], cancer [21], amoebic dysentery, different urinary disorders, cystitis, and gonorrhea [22].Moreover, the pericarp of Mangosteen-fruit, as a potent antioxidant, is widely used against immunological diseases like arthritis, food allergies, and acne [23] that may modulate the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) expressions levels [17].Some research proved that Mangosteen has myocardial protective [24], neuroprotective [25], and hepatoprotective [26] effects in in vitro and in vivo investigations.Indeed, prenylated xanthones and dibenzo-γpyrone derivatives are the chief complexes in the Mangosteen fruit (Fig. 1) [27], which possess antioxidant, antibacterial, cytotoxic, and anti-proliferative activity in the in-vitro study [28].Structurally, xanthones have been classified in a unique class of polyphenols consisting of a tricyclic scaffold (C6-C3-C6), which is improved by hydroxyl, isoprene, and methoxyl groups in addition to the A and B rings [29].Although their biological properties relate to the tricyclic scaffold, various bioactivities are associated with the nature or position of the several functional groups [30][31][32].Not only do fruit and pericarp contain xanthones, but also the leaves and bark of Mangosteen are riche of xanthones.Moreover, the research indicated that Mangosteen fruit has notable biological activity [33].In addition, the secondary metabolite of Mangosteen separately is classified in Table 1.
In this review, we have emphasized updating and comprehensive report on the toxicological investigations of G. mangostana extract and its ingredients on cell-based and animal models with neurological, inflammatory, and metabolic disorders and other toxicities, examining the molecular pathways suggested, and the biochemical factors described to give details about the effects observed and discussed.Taken together, these investigations indicate that Mangosteen and its bioactive xanthones may decline the harmful consequence of chemical and natural toxins and could act as a potential reagent for the treatment of various disorders such as Parkinson's disease, memory impairment, diabetes, hepatotoxicity, renal dysfunction, and cardiac injury.However, it is necessary to mention that differences in the efficacy of xanthone treatment may differ because of various route administration, dosages, and other dietary components.
The data is gathered from journals that published articles without publication time limitation until the end of December 2022.The keywords used were "protective, or ameliorative," "toxin, toxic, toxicity, nephrotoxic, radiation, cardiotoxic, hepatotoxic or neurotoxic" with "Mangosteen, Mangostin, Mangostana".We search through different websites such as Google Scholar (n = 110), PubMed (n = 126), and Web of Science (n = 9).Articles were written in English language and selected according to inclusion and exclusion.
A toxin, as a harmful substance, is generated in living cells or organisms.Natural toxins are often identified from other chemical factors because of their biological roots [34].Many types of research proved that Mangosteen has a beneficial effect on many natural toxins such as poxvirus, Staphylococcus aureus, and various natural toxins (Table 2).

ANTIBACTERIAL EFFECTS OF MANGOSTEEN AND ITS INGREDIENTS
Recently, the new antimicrobials' scarceness, as well as elevating antibiotic resistance, has been a severe challenge in the health system, making the demand for practical, affordable, and novel medicines for microbial infection treatment, mostly in developing countries [35,36].Some herbal medicines are highly efficient in bacterial infection therapies.Mainly, Mangostin has a magical potential to produce impressive secondary metabolites by elevating the related cytokines [37].
Hydroxyapatite (Hap) has a calcium phosphate structure with biomedical applications in dentistry and orthopedics.In some cases, Staphylococcus and Enterobacter cause infection in postoperative orthopedic surgeries after the implantation of porous Hap and slow down the improvement of wounds [41,42].Therefore, to control debridement, remove the implants, and inhibit this microorganism, Chaiarwut et al. surveyed Mangostin-coated Hap granules to prevent bacteria (Escherichia coli, Acinetobacter baumannii, and Staphylococcus aureus) persistence in chronic or long-term infections [41].Mangostin-coated Hap granules in a dosedependent manner (0.05 and 0.1 mg/mL of Mangosteen extract) decreased the growth of bacteria during 24 h, reaching 99.99% bacterial diminution without any toxicity against calvaria-derived pre-osteoblastic (MC3T3-E1) cells and calcium deposition [41].Another study revealed that Mangosteen extract exhibits anti-bacterial activities, and its nanoforming compounds (α-Mangostin-AgNPs, Mangosteen-AgNPs) inhibit the gram-positive and gram-negative bacterial strains.The evaluation of 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2′-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid (ABTS) free radicals, as an antioxidant activities evaluation manner, showed that Mangosteen-AgNPs and α-Mangostin-AgNPs were able to inhibit the ABTS and DPPH free radical with IC 50 value of 56.3 and 36.5 μg/mL.In addition, its effectiveness on gram-positive strains' growth inhibition was more than gram-negative strains' growth inhibition, with the least inhibitory effect against P. aeruginosa and E. coli [42].Furthermore, it has been proved that the ABTS radical scavenging ability remarkably relates to the number of hydroxyl groups, regardless of their location in the phenolic compounds [43].
Therefore, all research proved that Mangosteen extract and its ingredients have anti-bacterial activities, such as α-Mangostin glycosides, which are soluble in water [44].The investigation revealed that α-Mangostin glycosides (50 μg/disc) inhibited Micrococcus luteus (M.luteus), B. subtilis, and S. aureus growth.In addition, gram-negative bacterial strains in this study were resistant due to their outer lipopolysaccharide layer thickness.Therefore, the α-Mangostin glycopyranosides could band to a specific site on the bacteria's cell wall to stimulate the antibacterial effects [45].Tuberculosis (TB), a deadly human disease, has been considered a serious threat to humans worldwide in all age groups caused by Mycobacterium tuberculosis [46].Interaction between macrophages and host T-cells affects Mycobacterium tuberculosis (MTB) progression, adjusted by cytokines [47].In active TB individuals, interferon-gamma (IFNγ) is generated by activating natural killer cells (NK cells), CD8 + T-cells, and CD4 + T-cells.As a result, IFN-γ actives the macrophages and elevates the elimination of intracellular MTB [48,49].However, Il-10 has a suppression effect on immunogenicity against TB by reducing the IFN-γ expression level [50] (Fig. 2).Generally, balance among pro-and anti-inflammatory cytokines adjusts the severity of pathological damage that is relayed to the rate of bacteria in granulo- ma [51].Thus, producing new materials is necessary to prevent and treat this disease.Therefore, an in vivo study on infected mice (with MTB multidrug-resistant) revealed that the increased IL-10 levels were reduced by 6.95 mg/kg of α-Mangostin for seven days.Moreover, it can increase the IFN-γ expression.In addition, its treatment with α-Mangostin can decrease the severity and colonies of bacteria.Therefore, Mangostin xanthan has adjuvant therapy and immunomodulatory effects on TB [52].

MANGOSTEEN AND ITS INGREDIENTS' EF-FECTS ON LIPOPOLYSACCHARIDE-INDUCED TOXICITIES
Lipopolysaccharide (LPS) is a component of the cell wall of gram-negative bacteria that triggers the initiated signaling cascade for the expression of cytokines (TNF-α, IL-6, iNOS, and NF-κB) as well as cyclooxygenase 2 (COX2) LPS upregulates prostaglandin E 2 (PGE 2 ) and nitric oxide (NO) [53].Also, the induced oxidative stress biomarkers via nitrogen (RNS) or reactive oxygen species (ROS) have a prominent role in the pathogenesis stimulated by LPS [54].Hence, the antioxidant effect of Mangostins against LPS-induced oxidative stress has been studied in many in vitro and in vivo studies that are evaluated in Table 3 [55].
In dentistry, bone healing notably depends on the early inflammation stage with systemic and local responses against nasty stimuli.The previous study on α-Mangostin suggested that it was able to improve osteoblastic differentiation against LPS administration.Therefore, the up-regulated IL-1α (in LPS-induced toxicity cells) was decreased via 5 μg/ml of α-Mangostin.However, the suppressed ALP in LPS-induced toxicity in osteoblast cells was increased by α-Mangostin [56].Another investigation revealed that α-Mangostin elevates the Human nucleus pulpous cells (NPCS) viability infected by LPS.In addition, α-Mangostin down-regulated the expression levels of NLRP3 inflammasome (NOD-, LRR-and pyrin domain-containing protein 3), ASC (the modifier molecule apoptosis-depended specklike protein including a CARD), pro-caspase-1, IL-18 as well as IL-1β.Moreover, treatment with α-Mangostin notably suppressed apoptotic cell death, p-p65/p65, and nuclear p65 levels in NPCs compared to treatment with the LPS group.Also, it not only decreased the Bax and caspase-3 expression but also increased the level of Bcl-2 expression in α-Mangostin-treated NPCs.It is necessary to mention that NF-κB inhibition via pyrrolidine dithiocarbamate (PDTC) boosted the suppressed effects of α-Mangostin on apoptosis as well as activation of NLRP3 inflammasome in NPCs.So, α-Mangostin protects NLRP3 inflammasome-assessed apoptosis in LPS-induced NPCs via NF-κB signal adjusting (Fig. 3) [57].Tianhua Fu et al. investigation proved that α-Mangostin (12.5 and 25 mg/kg) has a hepatoprotective effect on LPSinduced acute liver failure in mice via the reduction in MDA, TNF-α, aspartate transaminase (AST), serum alanine aminotransferase (ALT), interleukin-1β, -6 levels.In contrast, it can improve hepatic glutathione (GSH), catalase (CAT), superoxide dismutase, and (SOD) activities.In addition, it could down-regulate NF-κB and toll-like receptor 4 (TLR4) expression.In contrast, α-Mangostin stimulated the heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression levels.Moreover, α-Mangostin has hepatoprotective effects on LPS-induced liver dysfunction via stimulating the Nrf2 (for antioxidant induction defense) and suppressing the TLR4 signaling pathway(for producing anti-inflammatory effects) [58].

ANTIVIRAL EFFECTS OF MANGOSTEEN AND ITS INGREDIENTS Α-MANGOSTIN
Investigations showed that the antiviral functions of Mangosteen are related to the polyphenolic compounds (xanthones), such as α-Mangostin and γ-Mangostin, via various mechanisms of action, such as inhibiting the reverse transcriptase and interfering with other replication processes [23,59].In fact, the section aims to review data on the antiviral activities of Mangosteen and its ingredients for managing viral diseases (Table 3).
The evaluation of the Mangosteen effect on avian pox virus (APV) revealed that ovo incubation of Mangosteen (1.5% and 3% w/v at 0.1 mL/egg) represses APV via decreasing pock lesions on the chorioallantoic membrane of the embryonated chicken eggs [60].Moreover, an in-silico study suggested that the α-Mangostin notably inhibits the main protease enzyme in HIV-1 (human immunodeficiency virus-1) [61][62][63] and COVID-19 (The main therapeutic target of COVID-19) [64].Furthermore, the in vitro cell assay investigation of α-Mangostin (8 µM under the co-treatment condition) inhibited the dengue virus growth.Then in-silico study for detecting the inhibiting mechanism exhibited that α-Mangostin can stick with multiple dengue virus protein objects (glycoprotein E, NS5 methyl-transferase, and NS2B-NS3 protease).Therefore, the results indicated that it could inhibit the production of the dengue virus during the replication cycle.Also, they introduced it to use as a prophylactic and therapeutic agent [65].Another designed assay proved that α-Mangostin inhibits the rotavirus replication after 1-2 hours but cannot detect the activated antiviral signaling pathways from the compounds that block the virus replication cycle.In addition, it stimulates NF-κB activation and IL-8 expression.Hence, it can reduce rotavirus infectivity [66].As a result, Mangosteen and its ingredients have beneficial and curative properties on viral diseases by different mechanisms of action, including blocking the viruses' replication cycle, virus growth, decreasing pock lesions, inhibiting the main protease enzyme, and priming the immune system against viruses.

ANTI-PARASITE EFFECTS OF MANGOSTEEN AND ITS INGREDIENTS Α-MANGOSTIN
The parasite is an organism that lives in or on the host for feeding.Human parasites are categorized into protozoans, helminths, and ectoparasites.They are usually transferred to their hosts by ingesting infected water/food or biting an arthropod as an intermediate host or a vector [67].This section evaluates some of them and their interaction with Mangosteen and its ingredients (Table 4).
Opisthorchis viverrini (O.viverrini) infection is produced by metacercariae of O. viverrini in raw cyprinid fish.After ingestion, the liver fluke movement to the biliary tract causes several hepatobiliary disorders such as cholangiocarcinoma  (CCA), cholangitis, lithiasis, and hepatitis [68].The investigation of α-Mangostin on O. viverrini revealed that α-Mangostin (142.04 μg/ mL) has antioxidant activities.Furthermore, histopathological evaluation of the hepatobiliary system showed that α-Mangostin admiration for 45 days could suppress the inflammatory cells surrounding the hepatic bile duct.In addition, in the adult O. viverrini, the body size was smaller, and egg production was reduced in Mangosteen-treated hamsters compared to the control group [69].
Nilaparvato lugens Stat., brown planthopper (BPH), is a common devastating insect pest in rice farms and can cause the loss of rice crops.Topical spraying of G. mangostana L. (with LC 50 of 4.5% w/v) and α-Mangostin (LC 50 of 5.44% w/v) as an alternative control agent against BPH Thailand strain, which affects various stages of nymphal and adult BPH.It has been shown that the extract and its active constituent α-Mangostin spraying had no dermal irritation and intoxication but exhibited eye irritation for one day (Table 4).In fact, glutathione-s-transferase (GST), carboxylesterase, and acetylcholinesterase are the main detoxification enzymes observed after 24 hours of exposure.On the other hand, toxicity values (LC 50 ) of Mangosteen extract elevated in each generation.Moreover, The LC 50 rates for each generation were estimated at 4.22-6.67after continuously spraying.Therefore, Mangosteen pericarp extract is an alternative insecticide against BPH, which is effective without environmental pollution and resistant to BPH [70,71].
Malaria, as one of the parasitic tropical diseases, is routinely treated with aminoquinolines, antifolates, artemisinin derivatives, and the hydroxyl naphthoquinone atovaquone [72].The mechanism of this parasite is described in Fig. ( 4) [73].Unfortunately, the adverse effects of these compounds and the economic burden motivated the researchers to investigate other alternatives or sensitizers for medications.The antimalarial mechanism of Mangosteen is not clear yet, but its hydros show potent anti-plasmodial activities by inhibiting hemozoin production.Hemozoin is produced from blood digestion by some blood-feeding parasites like plasmodium.Because of free heme toxicity on parasites, it is converted to an insoluble crystalline called hemozoin and is known as a malaria pigment [74,75].The in vitro investigation of Mangosteen extract was performed against chloroquine-sensitive (strain 3D7) and chloroquine-resistant (strain K1) Plasmodium falciparum (P.falciparum).Median (range) IC 50 values of the α-Mangostin and 9-hydroxy calabae for strain 3D7 vs. strain K1 clones were 17.9 (15.7.0-20.0) vs. 9.7 (6.0-14.0)μM, 1.5 (0.9-2.1) vs. 1.2 (1.1-1.6)μM, respectively.Analysis and combination index of α-Mangostin with 9-hydroxy caliber combination showed the synergistic antimalarial activity in both clones 3D7 and K1 strains [76].Another research showed that Mangosteen had a weak and moderate antiplasmodial activity with inhibiting concentration (IC50) (range) values of 11.12 (10.94-11.29)and 7.54 (6.80-7.68)µg/ml.Nevertheless, in this study, the Median (range) parasite density in the mice treated with 250, 500, 1000, and 2000 mg/kg of the Mangosteen extract for 14 d was 11.4 (9.49-13.8),11.6 (9.9-12.5),11.7 (10.6-12.8),10.9 (9.4-11.6)that is very low compared to the control group.Therefore, Mangosteen had weak antimalarial properties in this study, which may be due to insufficient absorption of the active complexes [77].
Caenorhabditis elegans (C.elegans), as a multicellular organism model for basic medical and biological study, is a kind of nematode that is used to test a potential anti-parasitic effect of α-Mangostin.The investigation indicated that α-Mangostin decreased the growth of the C. elegans flock (LC 50 : 3.8 ± 0.5 μm), similar to mebendazole effects [78].Therefore, according to the mentioned contents, Mangosteen and its xanthones can be used as an alternative therapy against various parasites.

EFFECTS OF MANGOSTEEN AND ITS INGREDI-ENTS AGAINST FUNGAL TOXICITIES
Candida albicans (C.albicans) growth in dentures, as a yeast biofilm, is a common disease in dentistry.Therefore, the in vitro investigation of α-Mangostin (concentration of ≥ 2,000 μg/ml) decreased the germ tube formation and the C. albicans adhesion to denture compared with clotrimazole (a topical anti-fungal treatment) that was similar [79].In some studies, the efficacy of α-Mangostin may happen through the destruction of mitochondrial energy metabolism [80].Aphanomyces invadans (A.invadans), Achlya bisexualis (A.bisexualis), and Saprolegnia diclina H3 (S. diclina H3), as aquatic fungi, belong to the Saprolegniaceae family that could make infection the fish or eggs like Saprolegniasis [81].α-Mangostin with 125, 250 ppm for A. invadans, 250 ppm for A. bisexualis, and 125 ppm for S. diclina H3 could cause malformed growth of hypha, with the dense and short branches in the inhibition zone of mycelium.Also, α-Mangostin (500, 1000 ppm) could inhibit the zoospores' growth and had toxic effects on them [82].Therefore, the low toxicity, rapid and robust properties of the anti-fungal properties of Mangosteen and its ingredients make it an alternative candidate treatment.However, the results of in vivo and in vitro studies' significance must be verified by clinical research and must be investigated.

EFFECTS OF MANGOSTEEN AND ITS INGREDI-ENTS AGAINST ARTHROPODS
As an important pest to most agricultural products, the rice weevil Sitophilus oryzae L. destroys about 70% of agricultural crabs yearly [83].After a whole drilling into a seed or grain kernel, the female puts in a single egg and seals.The development of larva and pupation is performed in the seed or grain kernel.At last, the seed or grain is left after 2-4 days.Therefore, it damages the rice or grain [84,85].The in vitro study revealed that the peel of Mangosteen extracts with LC 50 : 4.91 ± 1.19% w/v for 12 hours down-regulated the esterase and GST expressions in lived rice weevil [86].Also, another investigation revealed that Mangosteen extract (LC 50 : 30.1 µg/ml) and α-Mangostin (LC 50 : 19.4 µg/ml) had substantial toxicity against the larvae of Aedes aegypti [87].The results suggest that Mangosteen and related ingredients should be utilized for their potential property for controlling insects/arthropods and associated diseases.

EFFECTS OF MANGOSTEEN AND ITS INGREDI-ENTS AGAINST IONIZING RADIATION
Exposure to ionizing radiation (IR) triggers the complex systemic cascade as well as tissue-specific reactions that produce damaging signal transduction, impair the cell's functions, and produce free radicals [88].ROS or reactive nitrate species (RNS) stimulate NF-κB p65 translocation in the nucleus by phosphorylation of IκBα [89].So, they lead to the overproduction of IL-1β, IL-6, TNF-α and TGF-β activation [90].Administration of Mangosteen extract (500 mg/kg) for 30 days notably reduced the imbalance state of redox and toxicity motivated by γ-rays in liver tissues.Furthermore, it downregulates the ameliorated TGF-β1, MDA, NO, ALT, AST, ALP expressions, and NF-κB transcriptional factor and upregulates the SOD and CAT expressions.Mangosteen also had a suppressing effect on biomarkers such as CRP, TNF-α, and IL-6.These alterations make a proliferating improvement in cell nuclear antigen, which is expressed in the cell nuclei and is essential for DNA repair/synthesis [91].As a result, Mangosteen could improve oxidative damage, proapoptotic alternations, and inflammations induced by IR.

MANGOSTIN AND ITS CONSTITUENTS' EFFECTS ON H 2 O 2 -INDUCED TOXICITY
Mangosteen and its ingredients have many beneficial effects against many chemical agents, including pesticides, chemicals, and heavy metals, as explained below (Tables 5  and 6).
H 2 O 2 induces cell death in biotic and abiotic stress and causes ROS generation [92,93].ROS directly affects mitochondrial morphology and triggers programmed cell death [94].Moreover, H 2 O 2 can change the VEGF expression and its receptors, as well as the transcription factor of NF-κB in endothelial cells [95].The investigation revealed that hydroethanolic Mangosteen extract (320 μg/mL) for up to four hours could protect and improve DNA damage of H 2 O 2induced oxidative stress in human leukocytes [96].In another experiment, α-Mangostin (10 and 30 µM) potentially inhibited lipid peroxidation (LPOs) and oxyhemoglobin oxidation pathways and enhanced the cell-protective ability on H 2 O 2 -induced acute oxidative stress in the erythrocytes [97].The study by Jittiporn et al. revealed that Mangosteen (1, 5, and 10 μg/ml) inhibited H 2 O 2 -induced ROS formation and cell death in human endothelial cells (Table 5).Also, it attenuated p38 MAPK, poly (ADP-ribose) polymerase-1, and caspase 3 cleavage [98].Briefly, all investigation demonstrates that Mangosteen and its ingredients have antiapoptotic effects on H 2 O 2 -triggered cell death by preventing ROS formation.Many studies explained the antitoxic effects of Mangosteen and its xanthones against various toxic compounds in Table 5.

MANGOSTEEN AND THE EFFECTS OF ITS INGREDIENTS ON DRUG TOXICITIES 10.1. Cisplatin
As a known anti-tumor activity, cisplatin triggers several signal transduction pathways for inducing apoptosis via interaction with DNA to create the DNA adducts [99,100].Many reasons are reported for cisplatin resistance, such as elevating inactivation via thiol-molecules, repair of damaged DNA/its tolerance, creation of intracellular accumulation, upregulating of apoptosis inhibitors (un-adjusted cell signaling pathways, and surviving) (Fig. 5) [99].In addition, cytoprotective compounds such as α-Mangostin may diminish its adverse effects (nephrotoxicity, neurotoxicity, and ototoxicity).α-Mangostin (2.5 µg/ml for 16 h) remarkably decreased the cisplatin-induced cytotoxicity and enhanced the apoptotic effects (Table 6).Whereas α-Mangostin at a concentration higher than 5 µg/ml did not show any cytotoxicity effect but inhibited 100% cell growth [101].It is worth mentioning that α-Mangostin is capable of enhancing the cytotoxic effects of cisplatin on cancer stem cells and tumor growth [102,103] through induction of mitochondrial apoptosis signaling and depolarization (over-expression of Bax, reduction of Bcl-2, Mcl-1 and caspase-9/3 activation) [104].

Streptozotocin
Streptozotocin (STZ), an approved drug by the Food and Drug Administration (FDA), was suggested for the therapeutic of metastatic cancer of the pancreatic islet cells.Because of its adverse effects, its usage was limited to patients whose disease could not be improved by surgery.STZ decreased the tumor size and hypoglycemia through the over-secretion of insulin [105].In the experimental animal study, STZ was used for inducing insulitis and diabetes (because of its high toxicity to beta cells) [106] and Alzheimer's disease [107].STZ, similar to glucose, causes transportation into the cell by the glucose transport protein GLUT2, which makes it toxic to beta cells as these kinds of cells have a large number of GLUT (Table 6).However, the other transport proteins are unable to transport the STZ [108,109].γ-Mangostin, as a pigment of G. mangostana, presents hydrogen atoms for neutralizing free radicals.Therefore, it can decrease oxidative stress, especially in damaged cells, because of its prolonged hyperglycemic states in renal proximal tubular cells and hepatocytes [110][111][112].The in vivo study revealed that administering γ-Mangostin in dosages of 1, 2 and 4 mg/kg reduces the creatinine and plasma BUN and can also curate the damaged renal proximal tubular cells in STZ-induced diabetes mice [113].The investigation of α-Mangostin on STZ-induced diabetes mice showed that α-Mangostin at doses of 2, 4, and 8 mg/kg decreased plasma creatinine and BUN (Table 6).Also, it had a curative effect on impaired renal proximal tubular cells of the kidney in diabetic mice [114].Hence, Mangosteen and its xanthones have been introduced as a high-potent antioxidant agent to prevent diabetes mellitus or clinical management or reduce the STZinduced adverse effects in patients (Table 6).

THE EFFECTS OF MANGOSTEEN AND ITS IN-GREDIENTS ON INSECTICIDE-INDUCED TOXICI-TIES
The use of a wide range of chemicals to destroy pests and weeds is needed to achieve better production in agriculture (Table 6).Nevertheless, this compound's over-use causes widespread concern over its adverse health effects.Currently, pesticides are different in their mechanism of action, uptake, metabolism, elimination from the body, and human/animal toxicity.In addition, the active ingredients create adverse effects and contain impurities, solvents, carriers, emulsifiers, carriers, and other product constituents (Table 6) [115].

Abamectin
As an insecticide and anthelmintic compound, abamectin is naturally produced by Streptomyces avermitilis [116].The insecticide activity of abamectin is induced by interference in insects' nervous systems during different developmental stages and stimulates the glutamate-gated chloride channel [117].Its metabolism occurs by cytochromes P450.Furthermore, the neurotoxicity effects of abamectin are induced by apoptosis and oxidative stress.The administration of α-Mangostin (20 mg/kg) at 6-19 gestational days reduced the developmental neurotoxicity of abamectin via lowering the levels of NO and MDA and increasing the level of GSH, GST, SOD, CAT biomarkers, catecholamine's as well as apoptosis-proteins (with the regulation of the reelin and nestin genes).It is suggested that the neuroprotective efficacy of α-Mangostin occurs via transcription regulation of reelin and nestin (Table 6).Also, it regulated the serotonin and dopamine concentrations in the fetal brain of rats that were induced neurotoxicity via abamectin [118].

Rotenone
As an insecticide and pesticide, rotenone belongs to the rotenoids family, which is a colorless, odorless, crystalline isoflavone compound [119].Recently, rotenone has been widely used to induce Parkinson's disease in rodents, and its mechanism is explained in Fig. (6).Also, it interfered with oxidative stress, degeneration of dopaminergic neurons, and α-synuclein (α-Syn) accumulation by suppressing mitochondrial activity [120].
Parkinson's disease is a neurodegenerative disease in the elderly.Dopamine depletion is the major reason for motor symptoms caused by neuron degeneration in substantia nigra pars compacta via apoptosis.The Bcl-2 and caspase families adjust apoptosis through the intrinsic/extrinsic routes.Caspase-9 activation initiates the mitochondria-mediated pathway.Moreover, activation of caspase-8 triggers the cell death receptor-mediated pathway.Both initiator caspases affect executioner caspases (caspase-3 and -6).In turn, the executioner caspases cause apoptosis feature (DNA fragmentation).Proapoptotic factors, such as Bax, as a proapoptotic factor, are essential in dopaminergic neuron death in Parkinson's disease [121].

CONCLUSION AND RECOMMENDATIONS
Mangosteen and related active secondary metabolites xanthones (mainly α-, β-and γ-Mangostin) were identified in only a few plant families, lichens as well as fungi that displayed many pharmacological through various mechanisms with good safety in the major organ systems.Mangosteen, with other chemotherapeutic agents or alone, is an extraordinary therapeutic agent with lower toxicity.Moreover, the Mangosteen-related study displays a promising approach to treating complex diseases (Alzheimer's disease, Parkinson's disease, hepatotoxicity, and cardiac and kidney dysfunction).In addition, it is capable of reducing/inhibiting the harmful effects of chemical/natural toxic substances by savage the free radical generation.Mangosteen and its ingredients can treat acne and cause the skin to turn light by reducing the melanin concentration.According to the above studies, they can downregulate the cytokines expression such as TNF-α, MDA, SOD, IL-1β, IL-6, cyclo-oxygenase-1 (COX-1), and cyclo-oxygenase-2 (COX-2) expression levels.Therefore, we believe that Mangosteen and its xanthones can be used to treat certain viral and microbial diseases.In addition, these compounds have been studied for their possible effects on the new strain of viruses via molecular docking.However, low oral bioavailability and poor water solubility limit their therapeutic usage.This article reviews and discusses detailed information about Mangosteen's phytochemical and pharmacological properties and its ingredients against natural and chemical toxicities.However, excessive Mangosteen usage may have harmful consequences for people's health.However, there has not been any clinical study available that would demonstrate the efficacy of Mangosteen and its major xanthones, including α, β, and γ-Mangostin, in humanstoxicities.Therefore, xanthones or extracts of G. mangostana may have remarkable clinical potential against natural and chemical toxicities in humans; however, further in-vivo and clinical studies are needed.

AUTHORS' CONTRIBUTIONS
Roghayeh Yahyazadeh, Vafa Baradaran Rahimi, Ahmad Yahyazadeh, and Vahid Reza Askari wrote the first draft of the manuscript.All authors contributed to writing the project and read and approved the final manuscript submission.This study has been done by the authors mentioned in this article, and the authors will bear all responsibilities related to the contents of this article.

FUNDING
None.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.

Fig. ( 2 )
Fig. (2).Mechanism and effects of α-Mangostin on MTB infection.(A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. ( 3 ).
Fig. (3).The effect of α-Mangostin as a main xanthone of Mangosteen was evaluated on LPS-induced memory impairment and microglial dysfunction.(A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. ( 4
Fig. (4).Summarized Plasmodium spp.parasites' reproduction mechanism and life cycle in the human host, which is infected via an Anopheles spp.Mosquito bite.(A higher resolution/colour version of this figure is available in the electronic copy of the article).
Fig. (5).Evaluation of α-Mangostin against cisplatin-induced toxicities.(A higher resolution/colour version of this figure is available in the electronic copy of the article).
Fig. (6).The effect of rotenone on regulating the Nrf2 signaling pathway and induction of Parkinson's disease was proposed.Rotenone/ROS induces mitochondrial damage and change in mitochondrial proteins (PINK1/Parkin (PARK 2).A-synuclein aggregation and apoptosis are the main prognoses for the onset of Parkinson's disease.(A higher resolution/colour version of this figure is available in the electronic copy of the article).